Assessing Human Genome-wide Variation in the Massim Region of Papua New Guinea and Implications for the Kula Trading Tradition

The Massim, a cultural region that includes the southeastern tip of mainland Papua New Guinea (PNG) and nearby PNG offshore islands, is renowned for a trading network called Kula, in which different valuable items circulate in different directions among some of the islands. Although the Massim has been a focus of anthropological investigation since the pioneering work of Malinowski in 1922, the genetic background of its inhabitants remains relatively unexplored. To characterize the Massim genomically, we generated genome-wide SNP data from 192 individuals from 15 groups spanning the entire region. Analyzing these together with comparative data, we found that all Massim individuals have variable Papuan-related (indigenous) and Austronesian-related (arriving ∼3,000 years ago) ancestries. Individuals from Rossel Island in southern Massim, speaking an isolate Papuan language, have the highest amount of a distinct Papuan ancestry. We also investigated the recent contact via sharing of identical by descent (IBD) genomic segments and found that Austronesian-related IBD tracts are widely distributed geographically, but Papuan-related tracts are shared exclusively between the PNG mainland and Massim, and between the Bismarck and Solomon Archipelagoes. Moreover, the Kula-practicing groups of the Massim show higher IBD sharing among themselves than do groups that do not participate in Kula. This higher sharing predates the formation of Kula, suggesting that extensive contact between these groups since the Austronesian settlement may have facilitated the formation of Kula. Our study provides the first comprehensive genome-wide assessment of Massim inhabitants and new insights into the fascinating Kula system.     

Exercise Prevents Memory Impairment Induced by Arsenic Exposure in Mice: Implication of Hippocampal BDNF and CREB

High concentrations of arsenic, which can be occasionally found in drinking water, have been recognized as a global health problem. Exposure to arsenic can disrupt spatial memory; however, the underlying mechanism remains unclear. In the present study, we tested whether exercise could interfere with the effect of arsenic exposure on the long-term memory (LTM) of object recognition in mice. Arsenic (0, 1, 3, and 10 mg/ kg, i.g.) was administered daily for 12 weeks. We found that arsenic at dosages of 1, 3, and 10 mg/kg decreased body weight and increased the arsenic content in the brain. The object recognition LTM (tested 24 h after training) was disrupted by 3 mg/ kg and 10 mg/ kg, but not 1 mg/ kg arsenic exposure. Swimming exercise also prevented LTM impairment induced by 3 mg/ kg, but not with 10 mg/ kg, of arsenic exposure. The expression of brain-derived neurotrophic factor (BDNF) and phosphorylated cAMP-response element binding protein (pCREB) in the CA1 and dentate gyrus areas (DG) of the dorsal hippocampus were decreased by 3 mg/ kg and 10 mg/ kg, but not by 1 mg/ kg, of arsenic exposure. The decrease in BDNF and pCREB in the CA1 and DG induced by 3 mg/ kg, but not 10 mg/ kg, of arsenic exposure were prevented by swimming exercise. Arsenic exposure did not affect the total CREB expression in the CA1 or DG. Taken together, these results indicated that swimming exercise prevented the impairment of object recognition LTM induced by arsenic exposure, which may be mediated by BDNF and CREB in the dorsal hippocampus.     

Activating Brown Adipose Tissue for Weight Loss and Lowering of Blood Glucose Levels: A MicroPET Study Using Obese and Diabetic Model Mice

Purpose

This study aims at using ¹⁸F-FDG microPET to monitor the brown adipose tissue (BAT) glucose metabolism in obese and diabetic mouse models under different interventions, and study the therapeutic potential of BAT activation for weight loss and lowering of blood glucose in these models.

Methods

Obese mice were established by a high-fat diet for eight weeks, and diabetes mellitus(DM) models were induced with Streptozocin in obese mice. ¹⁸F-FDG microPET was used to monitor BAT function during obese and DM modeling, and also after BRL37344 (a β₃-adrenergic receptor agonist) or levothyroxine treatment. The BAT function was correlated with the body weight and blood glucose levels.

Results

Compared with the controls, the obese mice and DM mice showed successively lower ¹⁸F-FDG uptake in the interscapular BAT (P = 0.036 and <0.001, respectively). After two-week BRL37344 treatment, the BAT uptake was significantly elevated in both obese mice (P = 0.010) and DM mice (P = 0.004), accompanied with significantly decreased blood glucose levels (P = 0.023 and 0.036, respectively). The BAT uptake was negatively correlated with the blood glucose levels in both obese mice (r = −0.71, P = 0.003) and DM mice (r = −0.74, P = 0.010). BRL37344 treatment also caused significant weight loss in the obese mice (P = 0.001). Levothyroxine treatment increased the BAT uptake in the control mice (P = 0.025) and obese mice (P = 0.013), but not in the DM mice (P = 0.45).

Conclusion

The inhibited BAT function in obese and DM mice can be re-activated by β₃-adrenergic receptor agonist or thyroid hormone, and effective BAT activation may lead to weight loss and blood glucose lowering. Activating BAT can provide a new treatment strategy for obesity and DM.     

The EGFR/ErbB3 Pathway Acts as a Compensatory Survival Mechanism upon c-Met Inhibition in Human c-Met+ Hepatocellular Carcinoma

Backgroundc-Met, a high-affinity receptor for Hepatocyte Growth Factor (HGF), plays a critical role in tumor growth, invasion, and metastasis. Hepatocellular carcinoma (HCC) patients with activated HGF/c-Met signaling have a significantly worse prognosis. Targeted therapies using c-Met tyrosine kinase inhibitors are currently in clinical trials for HCC, although receptor tyrosine kinase inhibition in other cancers has demonstrated early success. Unfortunately, therapeutic effect is frequently not durable due to acquired resistance.MethodsWe utilized the human MHCC97-H c-Met positive (c-Met⁺) HCC cell line to explore the compensatory survival mechanisms that are acquired after c-Met inhibition. MHCC97-H cells with stable c-Met knockdown (MHCC97-H c-Met KD cells) were generated using a c-Met shRNA vector with puromycin selection and stably transfected scrambled shRNA as a control. Gene expression profiling was conducted, and protein expression was analyzed to characterize MHCC97-H cells after blockade of the c-Met oncogene. A high-throughput siRNA screen was performed to find putative compensatory survival proteins, which could drive HCC growth in the absence of c-Met. Findings from this screen were validated through subsequent analyses.ResultsWe have previously demonstrated that treatment of MHCC97-H cells with a c-Met inhibitor, PHA665752, results in stasis of tumor growth in vivo. MHCC97-H c-Met KD cells demonstrate slower growth kinetics, similar to c-Met inhibitor treated tumors. Using gene expression profiling and siRNA screening against 873 kinases and phosphatases, we identified ErbB3 and TGF-α as compensatory survival factors that are upregulated after c-Met inhibition. Suppressing these factors in c-Met KD MHCC97-H cells suppresses tumor growth in vitro. In addition, we found that the PI3K/Akt signaling pathway serves as a negative feedback signal responsible for the ErbB3 upregulation after c-Met inhibition. Furthermore, in vitro studies demonstrate that combination therapy with PHA665752 and Gefitinib (an EGFR inhibitor) significantly reduced cell viability and increased apoptosis compared with either PHA665752 or Gefitinib treatment alone.Conclusionc-Met inhibition monotherapy is not sufficient to eliminate c-Met⁺ HCC tumor growth. Inhibition of both c-Met and EGFR oncogenic pathways provides superior suppression of HCC tumor growth. Thus, combination of c-Met and EGFR inhibition may represent a superior therapeutic regimen for c-Met⁺ HCC.     

Effect of different iron loads on serum and tissue biochemical parameters and liver hepcidin mRNA abundance of neonatal piglets

Iron (Fe) is an essential and important trace element for animals. In order to study its metabolism and relationship with hepcidin, piglet models of Fe-deficiency and Fe-overload were established by intramuscular injection with different doses of Fe-dextran (150 mg Fe/ml) within 1 week of age. Twelve piglets were divided into three groups of four animals: deficiency, regular and overload group, receiving 0 ml, 1 ml and 6 ml Fe-dextran, respectively. The piglets were euthanised at the age of 7 days for analysis. The results showed that the Fe-concentrations in liver, spleen and serum of piglets in the overload group were higher than in the regular and deficiency groups (p < 0.05). In the overload group, several serum biochemical parameters, e.g. globulin, total bilirubin, total cholesterol, high density lipoprotein (HDL), malondialdehyde, glutathione peroxidase (GPx), peroxidase and xanthine oxidase were higher, while alkaline phosphatase (AKP) and triglycerides were lower, compared with the regular group (p < 0.05). The serum concentrations of AKP, total bilirubin and peroxidase in the deficiency group were lower, while HDL and GPx were higher, compared with the regular group (p < 0.05). Hepcidin mRNA abundance was 131 times lower in the liver of piglets with Fe-deficiency, and 7 times higher in the overloaded group than that in the regular group (p < 0.05). In conclusion, Fe-overload and deficiency would influence Fe-metabolism, serum biochemical indexes, oxidation state and hepcidin mRNA abundance in piglet liver.     

Different fermentation strategies by Schizochytrium mangrovei strain pq6 to produce feedstock for exploitation of squalene and omega‐3 fatty acids

Schizochytrium mangrovei strain PQ 6 was investigated for coproduction of docosahexaenoic acid (C22: 6ω‐3, DHA ) and squalene using a 30‐L bioreactor with a working volume of 15 L under various batch and fed‐batch fermentation process regimes. The fed‐batch process was a more efficient cultivation strategy for achieving higher biomass production rich in DHA and squalene. The final biomass, total lipid, unsaponifiable lipid content, and DHA productivity were 105.25 g · L^?1, 43.40% of dry cell weight, 8.58% total lipid, and 61.66 mg · g^?1 · L^?1, respectively, after a 96 h fed‐batch fermentation. The squalene content was highest at 48 h after feeding glucose (98.07 mg · g^?1 of lipid). Differences in lipid accumulation during fermentation were correlated with changes in ultrastructure using transmission electron microscopy and Nile Red staining of cells. The results may be of relevance to industrial‐scale coproduction of DHA and squalene in heterotrophic marine microalgae such as Schizochytrium .     

Hydrogen protects against hyperoxia-induced apoptosis in type II alveolar epithelial cells via activation of PI3K/Akt/Foxo3a signaling pathway

Oxidative stress is regarded as a key regulator in the pathogenesis of prolonged hyperoxia-induced lung injury, which causes injury to alveolar epithelial cells and eventually leads to development of bronchopulmonary dysplasia (BPD). Many studies have shown that hydrogen has a protective effect in a variety of cells. However, the mechanisms by which hydrogen rescues cells from damage due to oxidative stress in BPD remains to be fully elucidated. This study sought to evaluate the effects of hydrogen on hyperoxia-induced lung injury and to investigate the underlying mechanism. Primary type II alveolar epithelial cells (AECIIs) were divided into four groups: control (21% oxygen), hyperoxia (95% oxygen), hyperoxia + hydrogen, and hyperoxia + hydrogen + LY294002 (a PI3K/Akt inhibitor). Proliferation and apoptosis of AECIIs were assessed using MTS assay and flow cytometry (FCM), respectively. Gene and protein expression were detected by quantitative polymerase chain reaction (q-PCR) and western blot analysis. Stimulation with hyperoxia decreased the expression of P-Akt, P- FoxO3a, cyclinD1 and Bcl-2. Hyperoxic conditions increased levels of Bim, Bax, and Foxo3a, which induced proliferation restriction and apoptosis of AECIIs. These effects of hyperoxia were reversed with hydrogen pretreatment. Furthermore, the protective effects of hydrogen were abrogated by PI3K/Akt inhibitor LY294002. The results indicate that hydrogen protects AECIIs from hyperoxia-induced apoptosis by inhibiting apoptosis factors and promoting the expression of anti-apoptosis factors. These effects were associated with activation of the PI3K/Akt/FoxO3a pathway.     

The molecular species of phospholipids of the cold-water soft coral <Emphasis Type="Italic">Gersemia rubiformis</Emphasis> (Ehrenberg, 1834) (Alcyonacea,Nephtheidae)

The chemical structures and contents of 68 molecular species of ethanolamine glycerophospholipids (PE), choline glycerophospholipids (PC), serine glycerophospholipids (PS), and inositol glycerophospholipids (PI) were determined in the asymbiotic soft coral Gercemia rubiformis (Ehrenberg, 1834) from the Sea of Okhotsk by the method of tandem high-resolution mass spectrometry. The major molecular species were 16:1e/20:4 PE, 16:0e/20:4 PC, 20:1/24:5 PS, and 16:0/24:5 PI. This study showed a significant similarity of the polar lipidomes of G. rubiformis and tropical species of alcyonarians with symbiotic microalgae and revealed the basic characteristic of the polar lipidome of these alcyonarians. It was found that the 24:5n-6 and 24:6n-3 acids (chemotaxonomic markers of soft corals) concentrate in the acyl groups of the molecular species of PS and PI, which can be used as molecular lipid markers in the study of the symbiotic and trophic relationships of soft corals.